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| United States Patent |
5,002,771
|
|
Purkaystha
, et al.
|
March 26, 1991
|
Calcitonin suppository formulations
Abstract
Disclosed are rectal and vaginal suppository formulations comprising
calcitonin and caprylic acid monoglyceride in a pharmaceutically
acceptable suppository vehicle.
| Inventors:
|
Purkaystha; Abdur R. (Horsham, PA);
Gazdick; Gary G. (Wyndmoor, PA);
Dorrell; Jay E. (Wayne, PA);
Mozzone; Keith C. (Jeffersonville, PA);
Levin; Howard J. (Norristown, PA)
|
| Assignee:
|
Rorer Pharmaceutical Corp. (Fort Washington, PA)
|
| Appl. No.:
|
306696 |
| Filed:
|
February 3, 1989 |
| Current U.S. Class: |
424/433; 424/DIG.5; 530/307 |
| Intern'l Class: |
A61F 013/00 |
| Field of Search: |
424/433,DIG. 15
530/307
|
References Cited
U.S. Patent Documents
| 4434159 | Feb., 1984 | Sekine et al. | 514/808.
|
| 4597900 | Jul., 1986 | Orlowski et al. | 530/307.
|
| 4609640 | Sep., 1986 | Morishita | 530/350.
|
| 4746728 | May., 1988 | Orlowski et al. | 530/307.
|
Primary Examiner: Cashion, Jr.; Merrell C.
Assistant Examiner: Prater; P. L.
Claims
What we claim is:
1. A suppository composition for rectal or vaginal administration
comprising: from about 0.0004% w/w to about 0.200% w/w of a polypeptide
having calcitonin activity (as hereinbefore defined); from about 2.5% w/w
to about 50.0% w/w of caprylic acid monoglyceride; and suppository base
selected from the group consisting of mixtures of polyethylene glycols or
mixtures of mono-, di- and triglycerides of C.sub.10 to C.sub.20 chain
length.
2. The suppository composition of claim 1 wherein said polypeptide is
salmon calcitonin.
3. The suppository composition of claim 1 wherein said polypeptide is an
analog of salmon calcitonin.
4. The suppository composition of claim 1 wherein said. polypeptide is
selected from the group consisting of eel, bovin, porcine, ovine, rat,
chicken, and human calcitonins.
5. The suppository composition of claim 1 wherein said polypeptide is
obtained from natural sources.
6. The suppository composition of claim 1 wherein said polypeptide is
obtained by a synthetic route.
7. The suppository composition of claim 1 wherein said polypeptide has a
potency of from about 25 to about 10,000 international units per mg of
polypeptide.
8. A method for enhancing absorption, through the rectal or vaginal mucosal
membranes, of a polypeptide having calcitonin activity comprising: adding
from about 2.5% w/w to about 50.0% w/w of caprylic acid monoglyceride to a
composition comprising 0.0004% w/w to 0.200% w/w of a polypeptide having
calcitonin activity and a pharmaceutically acceptable suppository vehicle
in a quantity sufficient to make weight.
9. A method for the treatment of a patient suffering from diseases of
hyperparathyroidism, idiopathic hypercalcemia of infancy, Paget's disease,
vitamin D intoxication, or osteolytic bone metastases, said diseases
characterized by hypercalcemia and high phosphate concentrations in the
blood of said patient comprising: administering to said patient in need of
such treatment to effect control of at least one of said diseases an
effective amount of the composition of claim 1.
10. A suppository composition for rectal or vaginal administration
comprising: from about 0.005% w/w to about 0.05% w/w of a polypeptide
having calcitonin activity; from about 10% w/w to about 40% w/w of a
caprylic acid monoglyceride; and a pharmaceutically acceptable suppository
vehicle in a quantity to make weight.
11. The suppository composition of claim 10 wherein said polypeptide is
[N-alpha-X, 1,7 Di-Alanine (8-Y) Des-19-Leucine]) calcitonin, wherein X is
H, free amino or acyl-amino wherein acyl is derived from a carboxylic acid
having 1-10 carbon atoms, L-lactic acid or half amide of malonic,
succinic, glutaric, or adipic acids; and Y is L-valine, glycine,
L-methionine, L-alanine, L-leucine or L-isoleucine.
12. The suppository composition of claim 10 wherein said polypeptide is:
[N-alpha-X, 1,7-Di Alanine, Des-19-Leucine] calcitonin, wherein X is an
acyl derived from carboxylic acid having 1-5 carbon atoms.
13. THe suppository composition of claim 10 wherein said polypeptide is:
##STR29##
14. The suppository composition of claim 10 wherein said polypeptide is:
##STR30##
15. The suppository composition of claim 10 wherein said polypeptide is:
##STR31##
16. The suppository composition of claim 10 wherein said polypeptide is:
##STR32##
17. The suppository composition of claim 10 wherein said polypeptide is:
##STR33##
18. The suppository composition of claim 10 wherein said polypeptide is:
##STR34##
19. The suppository composition of claim 10 wherein said polypeptide is:
##STR35##
20. The suppository composition of claim 10 wherein said polypeptide is:
##STR36##
21. The suppository composition of claim 10 wherein said polypeptide is:
##STR37##
22. The suppository composition of claim 10 wherein said polypeptide is:
Ala-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Cly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu
-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-Nh.sub.2.
23. The suppository composition of claim 10 wherein said polypeptide is:
##STR38##
24. The suppository composition of claim 10 wherein said polypeptide is:
##STR39##
25. The suppository composition of claim 10 wherein said polypeptide is:
##STR40##
26. The suppository composition of claim 10 wherein said polypeptide is:
##STR41##
27. The suppository composition of claim 10 wherein said polypeptide is:
##STR42##
28. The suppository composition of claim 10 wherein said polypeptide is:
##STR43##
29. The suppository composition of claim 10 wherein said polypeptide is:
##STR44##
30. The suppository composition of claim 10 wherein said polypeptide is:
##STR45##
31. The suppository composition of claim 10 wherein said polypeptide is:
##STR46##
32. The suppository composition of claim 10 wherein said polypeptide is:
##STR47##
33. The suppository composition of claim 10 wherein said polypeptide is:
##STR48##
34. The suppository composition of claim 10 wherein said polypeptide is:
##STR49##
35. The suppository composition of claim 10 wherein said polypeptide is:
##STR50##
36. The suppository composition of claim 10 wherein said polypeptide is:
##STR51##
37. The suppository composition of claim 10 wherein said polypeptide is:
##STR52##
38. The suppository composition of claim 10 wherein said polypeptide is:
##STR53##
39. The suppository composition of claim 10 wherein said polypeptide is:
##STR54##
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel method of administering calcitonin
to patients and to formulations adapted for rectal and vaginal
administration. More particularly, the present invention relates to
calcitonin-containing pharmaceutical formulations containing therein
caprylic acid monoglyceride which promotes absorption of calcitonin and
thereby enhances its bioavailability.
2. Description of the Prior Art
The method of administration of pharmaceutically active calcitonin is
predominantly by injection, although efforts were made in the prior art to
use other modes of administration. While administration by injection is
acceptable for short-term therapy, administration by injection to patients
in need of long-term calcitonin therapy has serious problems. Not only is
it costly to patients to have physicians do the administration for
extended periods of time, but it is also painful and inconvenient. Nor can
calcitonin be given orally to patients since oral administration will
result in degradation of calcitonin.
Recently, the prior art has found that calcitonin may also be administered
via the rectal route; however, it was also found that certain absorption
promoters enhance absorption of calcitonin through the rectal mucosa and
as such may be used to advantage in calcitonin suppositories. Absorption
promoters that provided increased absorption include certain surface
active agents, amino acid derivatives, and certain nonsurfactant
adjuvenants, such as, ethylacetoacetate, dimethylethoxymethylenemalonate,
sodium salicylate and the like.
SUMMARY OF THE INVENTION
This invention relates to a suppository formulation comprising: from about
0.0004% w/w to about 0.20% w/w, and preferably from about 0.005% w/w to
about 0.05% w/w of calcitonin having a potency of about 25 to 6,000 IU/mg
of peptide or higher as hereinafter defined; from about 2.5% w/w to about
50.0% w/w and preferably from about 10% w/w to about 40% w/w of caprylic
acid monoglyceride and a pharmaceutically acceptable suppository vehicle.
The invention also relates to a method for increasing the absorption of
calcitonin through the rectal and/or vaginal mucosa by utilizing caprylic
acid monoglyceride in the suppository formulations. Hereinafter the
invention will be described with reference to rectal administration;
however, it is to be noted that, vaginal administration is intended to be
covered as well.
According to the invention, there is also provided a method for the
treatment of human patients suffering from diseases of
hyperparathyroidism, idiopathic hypercalcemia of infancy, Paget's disease,
vitamin D intoxication, or osteolytic bone metastases. Said diseases are
characterized by hypercalcemia and high phosphate concentrations and their
treatment is effected by decreasing serum calcium and phosphate
concentrations in the blood by rectal application of a calcitonin
containing composition to effect control of said diseases by transmucosal
action.
The term calcitonin as used herein means not only polypeptides having a
structure corresponding to one of the naturally occurring hormones, and
which may be naturally or synthetically produced, but also analogs thereof
and related synthetic peptides having calcitonin activity.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, suppository pharmaceutical
formulations are provided in which caprylic acid monoglyceride is
incorporated for enhancing the absorption of calcitonin through the rectal
mucosa. The composition of the formulations are described hereunder.
Calcitonin
Calcitonin is a polypeptide hormone involved in the control of calcium
metabolism in the body. All known natural calcitonin peptides contain an
amino acid sequence of 32 amino acids, of which the seven at the amino
terminal end of the peptide chain are held in a cyclic configuration by a
sulphur or carbon bridge and the carboxyl terminal residue consists of
proline amide. The natural calcitonins include the salmon, eel, bovin,
porcine, ovine, rat and human calcitonins. The detailed structure within
the peptide chain of the hormone varies among different species and while
the hormones, and their derivatives and analogues found in various species
are of interest for use in the present invention, salmon calcitonin is of
special interest in view of its relatively hydrophobic character and its
stability. Salmon calcitonin has the following formula:
##STR1##
In U.S. Pat. Nos. 3,926,938, 4,062,815, 3,929,758, 4,033,940, 4,336,187,
4,388,235, 4,391,747 and 4,401,593 are disclosed improved synthesis of
calcitonins including the salmon calcitonin referred to above.
Human, salmon and porcine calcitonins have been available for therapeutic
use for several years. For example, synthetic salmon calcitonin is
marketed by Armour Pharmaceutical Co. under the tradename CALCIMAR in a
sterile, lyophilized form reconstitutable for subcutaneous or
intravascular injection for the treatment of bone diseases.
The level of hypocalcemic activity of calcitonins varies from species to
species Salmon and chicken calcitonin have a potency of about 4,000 to
6,000 MCR (Medical Research Council) U/mg peptide; eel calcitonin about
2,000 to 4,000 MRC U/mg peptide; rat 400 MRC U/mg; while beef, sheep, hog
and man about 100 to 200 MRC U/mg peptide.
Calcitonin used by the present invention may be obtained from Armour
Pharmaceutical Co., from natural sources, or by synthetic routes known in
the art. The synthesis can be performed by classical peptide synthesis as
well as by solid phase synthesis.
In addition to the above-described calcitonins, the present invention
encompasses synthetic calcitonin peptides having biological activity of
the same type as those above-described Such synthetic calcitonins are
disclosed, along with processes for preparation thereof in the following
U.S. Pat. Nos.
______________________________________
4,388,235
4,604,238
4,391,747
4,605,514
4,397,780
4,605,515
4,401,593
4,606,856
4,414,149
4,622,386
4,444,681
4,622,387
4,451,395
4,622,388
4,469,636
4,632,978
4,497,731
4,639,509
4,497,732
4,639,510
4,528,132
4,639,511
4,537,716
4,650,854
4,597,900
4,659,804
4,604,236
4,732,969
4,604,237
4,746,728
______________________________________
Synthetic calcitonin analogues disclosed in these patents are incorporated
herein by reference as if set out in full herein. This list is not
intended to be exhaustive of all U.S. Patents covering synthetic
calcitonin analogues, but is representative of the analogues useful in the
present invention; nor is the invention limited to the compounds disclosed
in the listed patents.
In accordance for the foregoing, the following analogues of calcitonin
constitute specific active ingredients used in the various suppository
formulations of the present invention:
1. Des Asparagine-3-Calcitonins having the structures:
##STR2##
2. [16-Alanine] Calcitonins having the following structures:
##STR3##
3. Des .sup.2 -glycine .sup.8 -Des .sup.22 -Calcitonins having the
structures:
##STR4##
4. Des-13-Serine-Calcitonins having the following structures:
##STR5##
5. Des-21-Threonine-Calcitonins having the following structures:
##STR6##
6. [Gly.sup.2, Ser.sup.3, des-Tyr.sup.22 ] calcitonins having the following
structures:
##STR7##
7. Des-4-Leucine-Calcitonins having the following structures:
##STR8##
8. Calcitonin-(1-23)-Peptide Amides having the following structures:
##STR9##
9. [Des-1-Amino,8-Glycine) Calcitonins having the following structures:
##STR10##
10. [1,7-Di-Alanine] Calcitonins having the following structures:
##STR11##
11. 8-Methionine Calcitonins having the following structures:
##STR12##
12. Des-2-Serine, 3-Asparagine Calcitonins having the following structures:
##STR13##
13. G-Serine, Des-19-Leucine Calcitonins having the following structures:
##STR14##
14. [16,19-Di-Alanine] Calcitonins having the following structures:
##STR15##
15. (1-S-Acetamidomethyl Custeine, 7-Alanine) Calcitonins having the
following structures:
##STR16##
16. Des-19-Leucine - Calcitonin Analogs having the following structures:
##STR17##
17. (Bis-1,7-S-Acetamidomethyl-L-Cysteine) Salmon Calcitonins having the
following structures:
##STR18##
18. 8-Glycine, Des-19-Leucine-Calcitonins having the following structures:
##STR19##
19. Des-Leu.sup.16 -Calcitonins having the following structures:
##STR20##
20. Leucine.sup.22 - Calcitonins having the following structures:
##STR21##
21. Glycine - 8 Calcitonins having the following structures:
##STR22##
22. Glycine.sup.8 -D-Arginine.sup.24 Calcitonins having the following
structures:
##STR23##
23. L-Tyrosine.sup.21 Calcitonins having the following structures:
##STR24##
24. D-Arginine.sup.24 Calcitonins having the following structures:
##STR25##
25. Amides Analogues of Calcitonin having the following structures:
##STR26##
26. [N-alpha, 1,7-Di-Alanine, Des-19-Leucine] Calcitonins having the
following structures:
(a) [N-alpha-X, 1, 7 Di-Alanine (8-Y) Des-19-Leucine] calcitonins, wherein
X is H, free amino or acyl-amino wherein acyl is derived from a carboxylic
acid having 1-10 carbon atoms, L-lactic acid or half amide of malonic,
succinic, glutaric, or adipic acids; Y is L-valine, glycine, L-methionine,
L-alanine, L-leucine or L-isoleucine; and
(b) [N-alpha-X, 1, 7-Di-Alanine, Des-19-Leucine] calcitonins, wherein X is
an acyl derived from carboxylic acid having 1-5 carbon atoms.
27. 1,7-Di-Alanine, 8-Glycine, Des-19-Leucine Calcitonin having the
following structure:
##STR27##
28 N.alpha.-Propionyl, 1,7-Di-Alanine, Des-19-Leucine Calcitonin having the
following structure:
##STR28##
Caprylic Acid Monoglyceride
Absorption of calcitonin through the rectal mucosa is enhanced by the
presence of caprylic acid monoglyceride in the formulations of the present
invention. Caprylic acid monoglyceride or glyceryl caprylate may be
obtained by using a state-of-the-art method of preparation, or it may be
obtained from commercial suppliers, such as Dynamit Nobel under the
tradename Imwitor 308, which contains a mixture of mono-, di- and
triglycerides of caprylic acid with a typical ratio of 60:30:10. As used
in connection with the specification and claims of the present invention,
the term caprylic acid monoglyceride will be used to denote the
commercially supplied mixture of mono-, di-and triglycerides of caprylic
acid.
The Suppository Vehicle
The biologically/pharmacologically active calcitonin, as hereinbefore
defined, and caprylic acid monoglyceride are formulated with a suppository
vehicle adapted for rectal administration.
The suppository vehicle comprises a suppository base and certain
adjuvenants and additives suitable for making such, formulations. The
suppository base may be an aqueous or a fatty base material, the latter
being preferred mainly for ease of formulation and administration. The
fatty base material for use in the present invention includes: fatty oils
and fats, such as cocoa butter, palm oil, coconut oil, lard; waxes, such
as lanolin and vasoline; fatty acids, such as, oleic-, stearic-, and
lauric acids. We prefer to use a suppository base consisting essentially
of polyethylene glycols or mixtures of mono-, di-, and triglycerides of
fatty acids of C.sub.10 to C.sub.20 chain length. These are obtainable as
polyethylene glycol 1,000-8,000 (PEG=polymer of ethylene oxide, mol. wt.
1,000-8,000); cocoa butter, NF (fat obtained from the roasted seed of
Theobroma cacao); Suppocire AIX (semi-synthetic glycerides with
ethoxylated fatty acid esters containing 95% mono-, di- and triglycerides
and 5% polysorbate 65); Witepsol S 55 (semi-synthetic glycerides with
ethoxylated fatty acid esters containing 98% mono-, di- and triglycerides
and 2% PEG25 - cetyl stearyl alcohol) and Witepsol E75, supplied by
Dynamit Nobel, which is glyceryl esters of saturated fatty acids of chain
length C.sub.10 -C.sub.18.
The preparations of the present invention may also contain other additives,
such as antioxidants, stabilizers, viscosity builders, preservatives, and
the like. The concentration of these additives may vary according to the
particular additive used and the desired result sought The use of the kind
and concentration of additives are well within the ability of the skilled
artisan.
We contemplate three methods by which calcitonin can be incorporated into
the suppository system, namely, by the use of: (1) a buffer system, (2) a
gelatin stabilizer and (3) a bulking agent.
(1) According to this method, a buffer system is used as a carrier for the
calcitonin which provides stability for the same and facilitates its
admixture with the suppository vehicle.
The buffer system of the present invention preferably contains a sodium or
potassium phosphate/phosphoric acid buffer or a sodium or potassium
acetate/acetic acid buffer or a sodium or potassium citrate/citric acid
buffer in the range of 0.01 M to 0.5M and preferably in the range of 0.05
M to 0.2 M. The pH range of these buffers are between 2 0 to 8.0. This
concentration was found effective to provide stability of the dissolved
calcitonin in the vehicle.
(2) According to this method, the stabilizer system contains from about 1
to about 32% w/w of a gelatin hydrolized in a 0.9% w/w sodium chloride
solution or in purified water. The pH range of the stabilizer system is
between 2.0 to 8.0. This stabilizer system has been found very effective
in providing stability to the dissolved calcitonin.
(3) According to this method, a lyophilized or dry mixed bulking agent is
used as a carrier for calcitonin. The ratio of calcitonin to the bulking
powder is about 10 to 60,000 IU per mg. Examples of bulking agents
include, but are not limited to, gelatin, methionine, dextrose, sucrose,
mannitol, sorbitol, lactose, methyl cellulose, povidone, sodium chloride
and sodium acetate.
Preparation of the Formulations
In general the preparation of the formulations of the present invention is
as follows: the absorption promoter is melted with the suppository base;
antioxidants, such as BHA (bttylated hydroxyanisole, USP) and BHT
(butylated hydroxytoluene, USP) are added thereto and dissolved thereby
forming the suppository vehicle; calcitonin is dissolved in a buffer
solution or a stabilizer system or homogenously distributed in a bulk
powder mix and is blended with the suppository vehicle; and the
formulation is then poured into suitable suppository molds and allowed to
solidify.
Ingredients and amounts contemplated by the present invention are shown in
the general Formulas A, B and C.
______________________________________
Ingredient Quantity in mg
______________________________________
General Formula A
Calcitonin 25-6,000 I.U.
0.006-3.0
0.005-1.0M Acetate buffer, 1-100 .mu.l
Imwitor 308 37.5-750
BHA 0.015-1.5
BHT 0.015-1.5
Witepsol S 55 or Suppocire AIX or
1,500*
PEG 1,000-8,000 Qs Ad
General Formula B
Calcitonin 25-6,000 I.U.
0.006-3.0
1-100 .mu.l per gram of suppository base of:
1 to 32% w/w gelatin solution hydrolized
in 0.9% w/w sodium chloride or purified
water; pH adjusted to 2.0 to 8.0 with
HCl or NaOH.
Imwitor 308 37.5-750
BHA 0.015-1.5
BHT 0.015-1.5
Witepsol S 55 or Suppocire AIX or
1,500*
PEG 1,000-8,000 Qs Ad
______________________________________
*While 1,500 mg quantity suppository units are illustrated in General
Formula A, B and C, the quantity per unit may be in the range of 500 mg t
5,000 mg.
Preparative examples and typical formulations are set forth below. However,
it is to be understood that these examples are given by way of
illustration only and are not to be construed as limiting the invention
either in spirit or in scope as many modifications will be apparent to
those skilled in the art.
EXAMPLE 1
Imwitor 308 (promoter) is melted with Witepsol S 55 base at approximately
45.degree. C. The antioxidants, BHA and BHT, are added and dissolved. The
melted mixture is then allowed to cool to a slightly thicker mass.
Calcitonin (powder) is dissolved in 0.1 M acetate buffer (pH 4.0) to
contain 25 to 6,000 I.U. of salmon calcitonin in 37.5 .mu.l f the
solution. The calcitonin solution is added to the blended base and mixed.
The mixture is poured into suppository molds and allowed to solidify.
EXAMPLE 2
Imwitor 308 (promoter) is melted with Suppocire AIX base at approximately
45.degree. C. The antioxidants, BHA and BHT, are added and dissolved. The
melted mixture is then allowed to cool to a slightly thicker mass.
Calcitonin powder is dissolved in 0.1 M acetate buffer (pH 4.0) to contain
the desired calcitonin potency in 37.5 .mu.l of the solution The
calcitonin solution is added to the blended base and mixed The mixture is
poured into suppository molds and allowed to solidify.
EXAMPLE 3
Imwitor 308 (promoter) is melted with PEG 1450 base at approximately
50.degree. C. The antioxidants, BHA and BHT, are added and dissolved. The
melted mixture is then allowed to cool to a slightly thicker mass.
Calcitonin powder is dissolved in 1-32% gelatin/0.9% sodium chloride
solution (pH 3.2) to contain the desired I.U. of calcitonin in 37.5 .mu.l
of the solution The calcitonin solution is added to the blended base and
mixed The mixture is poured into suppository molds and allowed to
solidify.
EXAMPLE 4
Imwitor 308 (promoter) is melted with Witepsol E 75 or Suppocire AIX base
at approximately 50.degree. C. The antioxidants, BHA and BHT, are added
and dissolved. The melted mixture is then allowed to cool to a slightly
thicker mass. Calcitonin, as a calcitonin-mannitol lyophilized powder
mixture, is added to the suppository vehicle above and suspended
uniformly. The suspension is poured into suppository molds and allowed to
solidify.
EXAMPLE 5
______________________________________
Ingredient Quantity
______________________________________
SCT 45 I.U. in 37.5 .mu.l of a 0.1M
0.025 mg
acetate buffer (pH 4.0)
Imwitor 308 75 mg
BHA 0.15 mg
BHT 0.15 mg
Witepsol S 55 QS 1500 mg
______________________________________
EXAMPLE 6
______________________________________
Ingredient Quantity
______________________________________
SCT 500 I.U. in 37.5 .mu.l of a 0.1M
0.1 mg
acetate buffer (pH 4.0)
Imwitor 308 100 mg
BHA 0.15 mg
BHT 0.15 mg
Suppocire AIX QS 1500 mg
______________________________________
EXAMPLE 7
______________________________________
Ingredient Quantity
______________________________________
SCT 5,000 I.U. in 37.5 .mu.l of a 0.1M
0.050 mg
acetate buffer (pH 4.0)
Imwitor 308 700 mg
BHA 0.15 mg
BHT 0.15 mg
Witepsol S 55 QS 1500 mg
______________________________________
EXAMPLE 8
______________________________________
Ingredient Quantity
______________________________________
SCT 2,000 I.U. 0.075 mg
Mannitol, USP 75 mg
Imwitor 308 75 mg
BHA 0.15 mg
BHT 0.15 mg
Suppocire AIX QS Ad 1500 mg
______________________________________
EXAMPLE 9
______________________________________
Ingredient Quantity
______________________________________
SCT 400 I.U. 0.045 mg
Mannitol, USP 225 mg
Imwitor 308 750 mg
BHA 0.15 mg
BHT 0.15 mg
Witepsol E 75 QS Ad 1500 mg
______________________________________
EXAMPLE 10
______________________________________
Ingredient Quantity
______________________________________
SCT 100 I.U. 0.1 mg
Mannitol, USP 250 mg
Imwitor 308 500 mg
BHA 0.15 mg
BHT 0.15 mg
Suppocire AIX QS Ad 1500 mg
______________________________________
EXAMPLE 11
______________________________________
Ingredient Quantity
______________________________________
Calcitonin* in a 20% solution of gelatin
0.1 mg
hydrolized in 0.9% sodium chloride vehicle,
pH adjusted to 3.2 with HCl, 25 .mu.l/g
suppository base
Imwitor 308 600 mg
BHA 0.15 mg
BHT 0.15 mg
Suppocire AIX QS Ad 1500 mg
______________________________________
*1,7-Di-Alanine, 8glycine, Des19-Leucine Calcitonin
EXAMPLE 12
______________________________________
Ingredient Quantity
______________________________________
Bovine Calcitonin 400 I.U. in a 32% solution
0.1 mg
of gelatin hydrolized in purified water
vehicle, pH adjusted to 3.2 with HCl, 25 .mu.l/g
suppository base
Imwitor 308 75 mg
BHA 0.15 mg
BHT 0.15 mg
Suppocire AIX QS Ad 1500 mg
______________________________________
EXAMPLE 13
______________________________________
Ingredient Quantity
______________________________________
Calcitonin* in a 10% solution of gelatin
0.1 mg
hydrolized in 0.9% sodium chloride vehicle,
pH adjusted to 3.2 with HCl, 25 .mu.l/g
suppository base
Imwitor 308 750 mg
BHA 0.15 mg
BHT 0.15 mg
Witepsol S 55 1500 mg
______________________________________
*NPropionyl, 1,7Di-Alanine, Des19-Leucine Calcitonin
Suppository formulations of the present invention were tested for
hypocalcemic effect according to the following procedure:
Non-promoter and promoter containing salmon calcitonin suppositories were
administered rectally into rats and the rectums were sealed to avoid
expulsion of the suppositories. Blood samples were analyzed for serum
calcium levels at base line, 1, 2, 3 and 4 hours and percent serum calcium
level depressions from base line values were calculated and expressed as
hypocalcemic response. Reduction of serum calcium levels from base line is
a measure of salmon calcitonin activity.
Results obtained are illustrated in Table I. The formulation used is that
described in Example 5 with varying amounts of Imwitor 308.
TABLE I
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Effect of Promoter (Imwitor 308) in
Rectally Administered SCT Suppository to Rats
% Hypocalcemic Effect
Imwitor % (Post Administration)
in Suppository
1 Hour 2 Hour 3 Hour
4 Hour
______________________________________
0 19 18 11 9
2.5 23 16 3 2
5.0 28 25 15 8
10.0 26 34 38 32
25.0 26 34 35 34
50.0 28 35 37 35
______________________________________
While only certain embodiments of our invention have been described in
specific detail, it will be apparent to those skilled in the art that many
other specific embodiments may be practiced and many changes may be made
all within the spirit of the invention and the scope of the appended
claims.
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